Brenzavvy
bexagliflozin
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and monkey
“general toxicology studies (up to 6 months in rats and 9 months in monkeys)”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“Rats were administered bexagliflozin by oral gavage at doses of 1, 3, 10, or 30 mg/kg/day for 26 weeks”
Species: general tox
Rat and monkey
“general toxicology studies (up to 6 months in rats and 9 months in monkeys)”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Bexagliflozin produced no adverse effects on fertility in rats, on embryofetal toxicity in rats or rabbits, or on pre- and postnatal development in rats at clinically relevant exposures.”
Species: carcinogenicity
Sprague-Dawley rat and CD-1 mouse (2-year)
“The carcinogenic potential of bexagliflozin was evaluated in 2-year studies in Sprague-Dawley (SD) rats and CD-1 mice.”
Surrogate used in
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“Monkeys were administered bexagliflozin orally at doses of 2, 6, 20, or 60 mg/kg/day for 39 weeks.”
Pivotal GLP studies
General toxicology studies up to 6 months in rats and 9 months in monkeys
“general toxicology studies (up to 6 months in rats and 9 months in monkeys)”
Route in tox
Oral (gavage in rats, nasogastric intubation in monkeys)
“39-Week Nasogastric Intubation Toxicity and Toxicokinetics Study With Bexagliflozin in Cynomolgus Monkeys With a 4-Week Recovery Period”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosomal aberration, in vivo rat micronucleus and rat unscheduled DNA synthesis assays
“Bexagliflozin was not mutagenic or clastogenic with or without metabolic activation in the in vitro Ames bacterial mutagenicity assay, the in vitro CHO cell assay, an in vivo micronucleus assay in rats, and an in vivo unscheduled hepatic DNA synthesis study in rats.”
Carcinogenicity
2-year SD rat and CD-1 mouse: no neoplastic findings (about 54x and 135x clinical AUC)
“The carcinogenic potential of bexagliflozin was evaluated in 2-year studies in Sprague-Dawley (SD) rats and CD-1 mice. There were no neoplastic findings in mice and rats up to the highest doses tested (150 mg/kg/day for mice and 30 mg/kg/day for rats, representing approximately 135 and 54 times the clinical dose of 20 mg based on AUC, respectively).”
Reproductive & developmental
No adverse effects on rat fertility, rat or rabbit embryofetal development, or rat pre/postnatal development
“Bexagliflozin produced no adverse effects on fertility in rats, on embryofetal toxicity in rats or rabbits, or on pre- and postnatal development in rats at clinically relevant exposures.”
Safety pharmacology
No hERG effect up to 25 uM (99-fold MRHD Cmax)
“Bexagliflozin did not affect hERG channel-mediated potassium current in HEK293 cells up to the maximum tested concentration of 25 mcM (17,380 ng/mL, 99-fold MRHD based on clinical Cmax of 176 ng/ml)”
Genotox: Ames
Negative (Ames)
“Bexagliflozin was not mutagenic or clastogenic in the in vitro Ames bacterial mutagenicity assay, the in vitro mammalian chromosomal aberration assay, an in vivo micronucleus test in rats, and in vivo unscheduled hepatic DNA synthesis in rats.”
Genotox: in vitro mammalian
In vitro mammalian chromosomal aberration assay: negative
“Bexagliflozin was not mutagenic or clastogenic in the in vitro Ames bacterial mutagenicity assay, the in vitro mammalian chromosomal aberration assay, an in vivo micronucleus test in rats, and in vivo unscheduled hepatic DNA synthesis in rats.”
Genotox: in vivo
Rat micronucleus and rat hepatic unscheduled DNA synthesis: negative
“Bexagliflozin was not mutagenic or clastogenic in the in vitro Ames bacterial mutagenicity assay, the in vitro mammalian chromosomal aberration assay, an in vivo micronucleus test in rats, and in vivo unscheduled hepatic DNA synthesis in rats.”
Carcinogenicity model
2-year Sprague-Dawley rat and 2-year CD-1 mouse
“The carcinogenic potential of bexagliflozin was evaluated in 2-year studies in Sprague-Dawley (SD) rats and CD-1 mice.”
Carcinogenicity timing
2-year Sprague-Dawley rat and 2-year CD-1 mouse completed before the marketing application
“The carcinogenic potential of bexagliflozin was evaluated in 2-year studies in Sprague-Dawley (SD) rats and CD-1 mice.”
hERG / QT
No hERG effect up to 25 uM, 99-fold MRHD Cmax
“Bexagliflozin did not affect hERG channel-mediated potassium current in HEK293 cells up to the maximum tested concentration of 25 mcM (17,380 ng/mL, 99-fold MRHD based on clinical Cmax of 176 ng/ml)”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Brenzavvy don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: NOAEL was the highest dose tested in monkeys and rats (78x and 89x clinical AUC) (FDA integrated review, p. 87)
NOAEL / key findings
NOAEL was the highest dose tested in monkeys and rats (78x and 89x clinical AUC)
“In both monkeys and rats, the no observed adverse effect level (NOAEL) was the highest dose tested, which corresponded to 78 and 89 times the clinical dose of 20 mg, respectively, based on AUC.”
Risksopen answer page →
Immune & cytokine safety
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Biodistribution & persistence
Highest rat tissue levels in kidney, liver, adrenal, pancreas, harderian and preputial glands
“In a distribution study in rats, the kidney medulla and cortex, liver, adrenal cortex and medulla, pancreas, harderian gland, and preputial gland showed the highest bexagliflozin concentration between 4 to 12 hours postdose.”
Modality-specific risk
Juvenile renal findings; not recommended in second and third trimesters of pregnancy
“Based on the juvenile animal data, bexagliflozin is not recommended for use during the second and third trimester of pregnancy.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
- Lower Limb Amputation
- Volume Depletion
- Genitourinary Infections, including Urosepsis, Pyelonephritis, Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene), and Genital Mycotic Infections
- Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
Metabolic & endocrineNephrotoxicityInfections
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Brenzavvy don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: NOAEL was the highest dose tested in monkeys and rats (78x and 89x clinical AUC) (FDA integrated review, p. 87)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (nasogastric intubation) with 4-week recovery
“39-Week Nasogastric Intubation Toxicity and Toxicokinetic Study with Bexagliflozin in Cynomolgus Monkeys with a 4-Week Recovery Period”
Pivotal GLP studies
General toxicology studies up to 6 months in rats and 9 months in monkeys
“general toxicology studies (up to 6 months in rats and 9 months in monkeys)”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Bexagliflozin produced no adverse effects on fertility in rats, on embryofetal toxicity in rats or rabbits, or on pre- and postnatal development in rats at clinically relevant exposures.”
Reproductive & developmental
No adverse effects on rat fertility, rat or rabbit embryofetal development, or rat pre/postnatal development
“Bexagliflozin produced no adverse effects on fertility in rats, on embryofetal toxicity in rats or rabbits, or on pre- and postnatal development in rats at clinically relevant exposures.”
PPND / ePPND: when
PPND in rat (oral gavage) completed before the marketing application
“THR-1442-T-459: Oral Gavage Study for Effects on Pre- and Postnatal Development, Including Maternal Function, With Bexagliflozin in Rats”
Carcinogenicity
Species: carcinogenicity
Sprague-Dawley rat and CD-1 mouse (2-year)
“The carcinogenic potential of bexagliflozin was evaluated in 2-year studies in Sprague-Dawley (SD) rats and CD-1 mice.”
Carcinogenicity model
2-year Sprague-Dawley rat and 2-year CD-1 mouse
“The carcinogenic potential of bexagliflozin was evaluated in 2-year studies in Sprague-Dawley (SD) rats and CD-1 mice.”
Carcinogenicity timing
2-year Sprague-Dawley rat and 2-year CD-1 mouse completed before the marketing application
“The carcinogenic potential of bexagliflozin was evaluated in 2-year studies in Sprague-Dawley (SD) rats and CD-1 mice.”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL (highest dose) 78x (monkey) and 89x (rat) human AUC at 20 mg
“In both monkeys and rats, the no observed adverse effect level (NOAEL) was the highest dose tested, which corresponded to 78 and 89 times the clinical dose of 20 mg, respectively, based on AUC.”
NOAEL / key findings
NOAEL was the highest dose tested in monkeys and rats (78x and 89x clinical AUC)
“In both monkeys and rats, the no observed adverse effect level (NOAEL) was the highest dose tested, which corresponded to 78 and 89 times the clinical dose of 20 mg, respectively, based on AUC.”
Efficacy evidenceopen answer page →
Efficacy evidence
Diabetic db/db mouse and ZDF rat models: dose-dependent HbA1c reduction
“In diabetic mouse (db/db) and rat (ZDF) models, bexagliflozin 0.1 mg/kg to 3 mg/kg dose-dependently reduced HbA1c after four weeks of oral treatment at exposures equivalent to the clinical dose (Figure 3).”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
FDA: effectiveness evidence from in vitro human SGLT2 inhibition and glucosuria, glucose and HbA1c in healthy and diabetic animals
“Nonclinical evidence of effectiveness was obtained from in vitro studies evaluating the activity of bexagliflozin on human SGLT2, and from in vivo studies evaluating levels of glucosuria, blood glucose, and hemoglobin A1c (HbA1c) in healthy animals and/or diabetic animal models.”
Flexibilityopen answer page →
Flexibility accepted
No departure named in the public reviews.
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